Voltage-gated calcium channels are a major route of calcium translocation across the plasma membrane of excitable cells. These channels are also known as voltage-dependent calcium channels or VDCCs. Six types of calcium channels have been identified: T, L, N, P, Q, and R. Each channel has different voltage ranges and rates for activation and inactivation. T-type channels need only small depolarizations to be activated (low-voltage activated, LVA), while the other types require larger depolarizations (high-voltage activated, HVA).
Voltage-gated calcium channels are made up of subunits α1, β α2, δ. Of these the α1 subunit is the ion pore forming subunit to which the other subunits are auxiliary. β-subunits play an important role in the Ca2+ channel trafficking to the cell surface and modulate its biophysical properties. β-subunits have been found to affect all aspects of pore function including rates of voltage activation and deactivation. Among the β-subunit encoding genes, P/Q-type Cav2.1 and N-type Cav2.2 are the main channel subtypes on the presynaptic site and thus support neurotransmitter release. Four isoforms of the cytoplasmic β-subunit with a number of splice variants have been identified (β1, β2, β3 and β4). These isoforms show different tissue expression and subcellular localisation and have been correlated to associate with the different types of Voltage-gated calcium channels.
Intracellular calcium plays an important role in many biological processes such as calcium dependant neurotransmitter release, hormone secretion, muscle contraction and gene expression. More specifically, it is documented that abnormal levels of intracellular calcium create an imbalance in calcium homeostasis in a variety of cells, tissues and organs leading to many disorders. Cardiac and neural tissues are thought to be especially sensitive to calcium.
Voltage-gated calcium channels are thought to help control the intracellular flow of calcium. The conversion of the intracellular calcium flow by voltage-gated calcium channels is thought to impact a wide spectrum of biological responses and are implicated in several diseases, including ataxia, migraine, epilepsy, neurodegeneration, hypertension, cardiac disorders and diabetes. Currently there are several Calcium channel blockers used to treat some of these conditions. VGCC is associated with genetic diseases called “calcium channelopathies”, which include muscular, neurological and cardiac syndromes. Most of these diseases were attributed to gain and loss of function of Ca2+ channel activity. For instance, the familial hemiplegic migraine type 1 is associated with an increase in Cav2.1 current density
Compounds such as verapamil, isradipine, nefedipine, dilantizem and 1,4-dihydropine analogs of nefedipine interact with the L-type calcium channel to block calcium translocation and are widely used as antihypertensives, migraine treatment and in the treatment of certain vascular disorders. However, there are reports that therapeutic use of many calcium channel blockers is associated with potentially life-threatening side-effects. These include hypotension, constipation, decrease in insulin secretion leading to diabetes and heart block.
Other calcium channel blockers under development for use in disorders of the central nervous system and as analgesics include toxins that have been isolated from marine snails, scorpions, funnel web and tarantula spiders. The side effects and efficacy of such compounds are as yet unknown.
Only two compounds have been found to act as agonists of voltage gated calcium channels, a dihydropyridine derivative BayK 8644 and Glycerotoxin isolated from sea worms. Despite the anticipated therapeutic effects of these compounds such as stimulating insulin secretion in diabetic and pre-diabetic living beings there has been severe side effects such as dystonic neurobehavioural syndrome, hypertension and arrhythmia during in vivo studies using BayK 8644 resulting in halted development of such compounds.
There is a need for new agonists and antagonists capable of modulating voltage gated calcium channels to treat disorders associated with voltage gated calcium channels.
Dos or downstream of Stk11 kinase is a protein named by the position of its encoding gene in the chromosome 10. Only the C-terminal part of the protein was described and no function was established. Sequences analysis of mouse, rat and human EST clones together with classical library screening revealed a transcript of 3 kb encoding for a protein of 698 amino acids. No functional or structural region was identified.
The present invention seeks to provide novel modulators of voltage gated calcium channels for use in treating disorders related to voltage gated calcium channels.
General
Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. The invention includes all such variation and modifications. The invention also includes all of the steps, features, formulations and compounds referred to or indicated in the specification, individually or collectively and any and all combinations or any two or more of the steps or features.
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The present invention is not to be limited in scope by any of the specific embodiments described herein. These embodiments are intended for the purpose of exemplification only. Functionally equivalent products, formulations and methods are clearly within the scope of the invention as described herein.
The invention described herein may include one or more range of values (eg size, concentration etc). A range of values will be understood to include all values within the range, including the values defining the range, and values adjacent to the range which lead to the same or substantially the same outcome as the values immediately adjacent to that value which defines the boundary to the range.
Throughout this specification, unless the context requires otherwise, the word “comprise” or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. It is also noted that in this disclosure and particularly in the claims and/or paragraphs, terms such as “comprises”, “comprised”, “comprising” and the like can have the meaning attributed to it in U.S. Patent law; e.g., they can mean “includes”, “included”, “including”, and the like; and that terms such as “consisting essentially of” and “consists essentially of” have the meaning ascribed to them in U.S. Patent law, e.g., they allow for elements not explicitly recited, but exclude elements that are found in the prior art or that affect a basic or novel characteristic of the invention.
Other definitions for selected terms used herein may be found within the detailed description of the invention and apply throughout. Unless otherwise defined, all other scientific and technical terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the invention belongs.